Evaluation of azacitidine and entinostat as sensitization agents to cytotoxic chemotherapy in preclinical models of non-small cell lung cancer Journal Article


Authors: Vendetti, F. P.; Topper, M.; Huang, P.; Dobromilskaya, I.; Easwaran, H.; Wrangle, J.; Baylin, S. B.; Poirier, J. T.; Rudin, C. M.
Article Title: Evaluation of azacitidine and entinostat as sensitization agents to cytotoxic chemotherapy in preclinical models of non-small cell lung cancer
Abstract: Recent clinical data in lung cancer suggests that epigenetically targeted therapy may selectively enhance chemotherapeutic sensitivity. There have been few if any studies rigorously evaluating this hypothesized priming effect. Here we describe a series of investigations testing whether epigenetic priming with azacitidine and entinostat increases sensitivity of NSCLC to cytotoxic agents. We noted no differences in chemosensitivity following treatment with epigenetic therapy in in vitro assays of viability and colony growth. Using cell line and patientderived xenograft (PDX) models, we also observed no change in responsiveness to cisplatin in vivo. In select models, we noted differential responses to irinotecan treatment in vivo. In vitro epigenetic therapy prior to tumor implantation abrogated response of H460 xenografts to irinotecan. Conversely, in vitro epigenetic therapy appeared to sensitize A549 xenografts (tumor growth inhibition 51%, vs. 22% in mock-pretreated control). In vivo epigenetic therapy enhanced the response of adenocarcinoma PDX to irinotecan. Taken together, these data do not support broadly applicable epigenetic priming in NSCLC. Priming effects may be context-specific, dependent on both tumor and host factors. Further preclinical study is necessary to determine whether, and in which contexts, priming with epigenetic therapy has potential to enhance chemotherapeutic efficacy in NSCLC patients.
Keywords: controlled study; human cell; cisplatin; cancer combination chemotherapy; cancer growth; dose response; drug potentiation; monotherapy; nonhuman; gemcitabine; animal tissue; bortezomib; multiple cycle treatment; animal experiment; animal model; in vitro study; tumor xenograft; chemosensitivity; cancer model; docetaxel; irinotecan; drug dose escalation; cancer inhibition; epigenetics; tanespimycin; drug cytotoxicity; navelbine; drug sensitivity; azacitidine; non small cell lung cancer; epigenetic; entinostat; priming; human; article; ic50; a549 cell line; non-small cell lung cancer (nsclc)
Journal Title: Oncotarget
Volume: 6
Issue: 1
ISSN: 1949-2553
Publisher: Impact Journals  
Date Published: 2015-01-01
Start Page: 56
End Page: 70
Language: English
PROVIDER: scopus
PUBMED: 25474141
PMCID: PMC4381578
DOI: 10.18632/oncotarget.2695
DOI/URL:
Notes: Export Date: 2 March 2015 -- Source: Scopus
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  1. Charles Rudin
    495 Rudin
  2. John Thomas Poirier
    82 Poirier